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Author Spotlight: A Computational Approach to Decipher Amino Acid Preferences in Multispecific Protein-Protein Interactions
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Structure-based prediction of Ras-effector binding affinities and design of "branchegetic" interface mutations

Philipp Junk1, Christina Kiel2

  • 1Systems Biology Ireland, School of Medicine, University College Dublin, Dublin 4, Ireland; UCD Charles Institute of Dermatology, School of Medicine, University College Dublin, Dublin 4, Ireland.

Structure (London, England : 1993)
|May 11, 2023
PubMed

Insights

Researchers modeled 54 Ras-effector complexes to understand how Ras protein interactions are rewired. They identified mutations affecting binding, providing a systems-level view of this crucial cellular hub.

Area of Science:

  • Molecular Biology
  • Systems Biology
  • Structural Biology

Background:

  • Ras proteins are critical cellular hubs regulating cell fate.
  • Understanding Ras interactions with diverse effector proteins is essential but incomplete.
  • Detailed characterization of Ras-effector interactions is limited to a few key partners.

Purpose of the Study:

  • To structurally model Ras-effector complexes and predict binding affinities.
  • To identify mutations impacting Ras-effector binding energy.
  • To assess the systems-level impact of Ras interaction rewiring.

Main Methods:

  • Homology modeling using X-ray and AlphaFold2 templates to generate 54 Ras-effector complex models.
  • Supervised learning regressor to estimate binding affinities.
  • Systematic introduction of 'branchegetic' mutations to identify interface changes.

Main Results:

  • Generated structural models for 54 Ras-effector complexes.
  • Identified 200 interface mutations affecting binding energy with at least one complex.
  • Estimated binding affinities and quantified the impact of mutations on Ras interaction networks.

Conclusions:

  • Provided a quantitative understanding of Ras-effector interfaces.
  • Demonstrated the potential for rewiring interactions at the Ras hub on a systems level.
  • Highlighted the impact of Ras-effector interface properties on cellular systems.
Keywords:
AlphaFoldFoldXRasbranch pruningedgeticseffectorsenedgeticshomology modelinghubnetworks

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